Amino acid mimetic copolymers and medical devices coated with the copolymers

ABSTRACT

Biocompatible polymers are manufactured to include an amino acid mimetic monomer and one or more hydrophobic acrylate monomers. The amino acid mimetic monomers are selected to mimic the side chain of the amino acids asparagine or glutamine. The amino acid mimetic monomer can be a methacryloyl or acryloyl derivative of 2-hydroxyacetamide, 3-hydroxypropionamide, alaninamide, lactamide, or glycinamide. These amide functional groups offer the advantage of moderate hydrophilicity with little chemical reactivity. The amino acid mimetic monomer can be copolymerized with one or more hydrophobic acrylate monomers to obtain desired coating properties.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 11/942,705 filed on Nov. 19, 2007, the teaching of which isincorporated by reference in its entirety. U.S. application Ser. No.11/942,705 claims the benefit of U.S. Provisional Patent ApplicationsNos. 60/866,800, 60/866,802, 60/866,804, 60/866,805 60/866,798,60/866,797, 60/866,796, 60/866,792, all of which were filed on Nov. 21,2006, and all of which are hereby incorporated by reference in theirentirety. This application is related to co-pending U.S. patentapplication Ser. No. 11,942,695, entitled “Copolymers HavingZwitterionic Moieties and Dihydroxyphenyl Moieties and Medical DevicesCoated with the Copolymers”, co-pending U.S. patent application Ser. No.11/942,704, entitled “Methods of Manufacturing Copolymers withZwitterionic Moieties and Dihydroxyphenyl Moieties and Use of Same”,co-pending U.S. patent application Ser. No. 11/942,693, entitled“Zwitterionic Copolymers, Method of Making and Use on Medical Devices”,co-pending U.S. patent application Ser. No. 11/942,696, entitled“Methods for Manufacturing Amino Acid Mimetic Copolymers and Use ofSame”, co-pending U.S. patent application Ser. No. 11/942,700, entitled“Copolymers Having 1-Methyl-2-Methoxyethyl Moieties”, and co-pendingU.S. patent application Ser. No. 11/942,707, entitled “Methods forManufacturing Copolymers having 1-Methyl-2-Methoxyethyl Moieties and Useof Same”, all of which were filed on Nov. 19, 2007, and all of which arehereby incorporated by reference in their entirety. Co-pending U.S.patent application Ser. No. 11/939,512, filed Nov. 13, 2007, andco-pending application Ser. No. 11/562,338, filed Nov. 21, 2006 arehereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

1. The Field of the Invention

Embodiments of the invention relate to polymeric coatings for coatingimplantable medical devices. More particularly, embodiments of theinvention relate to acrylate copolymers that include monomers that mimicasparagine and glutamine.

2. The Related Technology

Implantable medical devices, including stents, can be coated withpolymers to give the implantable device beneficial properties when usedin living tissue. Implant coatings, particularly stent coatings,typically need to simultaneously fulfill many criteria. Examples ofdesirable properties for implant coating properties include: adhesion tothe implant (e.g., adhesion to stent struts) to prevent delamination;adequate elongation to accommodate implant deformation without bucklingor cracking; sufficient hardness to withstand crimping operationswithout excessive damage; sterilizability; ability to control therelease rate of a drug; biocompatibility including hemocompatibility andchronic vascular tissue compatibility; in the case of durable orpermanent coatings, the polymer needs to be sufficiently biostable toavoid biocompatibility concerns; processability (e.g. production ofstent coatings that are microns thick); reproducible and feasiblepolymer synthesis; and an adequately defined regulatory path.

Many methacrylate polymers exhibit several of the forgoing properties.However, some desired properties or combinations of desired propertieshave been difficult to achieve in methacrylate polymers. For example,homopolymers of hydrophobic methacrylates, including poly(n-butylmethacrylate) (PMBA), can have a low permeability for drugs of interest,leading to a slower drug release rate than desired.

Recently, efforts have been made to copolymerize traditionalmethacrylate monomers with other monomers to achieve a copolymer thathas the benefits of known methacrylate homopolymers and overcomes theirdeficiencies. One challenge to developing novel methacrylate copolymershas been achieving the desired mechanical properties, and controllingthe drug release, while maintaining biocompatibility. Goodbiocompatibility is essential for patient safety, necessary for deviceefficacy, and important for receiving regulatory approval to use thepolymer on an implantable medical device.

SUMMARY OF THE INVENTION

Embodiments of the invention relate to biocompatible polymers thatinclude an amino acid mimetic monomer and one or more hydrophobicacrylate monomers. The amino acid mimetic monomers are selected to mimicthe side chain of the amino acids asparagine or glutamine. Creatingsynthetic polymers that imitate nature is a form of biomimicry.Mimicking naturally occurring biomolecules is advantageous because itincreases the likelihood that the synthetic molecule will bebiocompatible. In one embodiment, the amino acid mimetic monomer is amethacryloyl or acryloyl derivative of 2-hydroxyacetamide,3-hydroxypropionamide, alaninamide, lactamide, or glycinamide. Theseamide functional groups offer the advantage of moderate hydrophilicitywith little chemical reactivity.

The amino acid mimetic monomer is copolymerized with one or morehydrophobic acrylate monomers to obtain the desired coating properties.The hydrophobic monomer provides mechanical strength and moderates waterswelling. The amino acid mimetic monomer provides a desired level ofhydrophilicity without compromising biocompatibility. The copolymers ofthe invention can be thermoplastic and mechanically robust, withoutcross-linking.

These and other advantages and features of the invention will becomemore fully apparent from the following description and appended claims,or may be learned by the practice of the invention as set forthhereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

To further clarify the above and other advantages and features of theinvention, a more particular description of the invention will berendered by reference to specific embodiments thereof which areillustrated in the appended drawings. It is appreciated that thesedrawings depict only typical embodiments of the invention and aretherefore not to be considered limiting of its scope. The invention willbe described and explained with additional specificity and detailthrough the use of the accompanying drawings, in which:

FIG. 1A illustrates an example of a stent coated with a copolymeraccording to one embodiment of the invention; and

FIG. 1B is a cross-section of a strut of the stent of FIG. 1A.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION I. Copolymers

The copolymers of the invention include a hydrophobic monomer and apolar monomer that mimics an amino acid. The combination of thehydrophobic monomer and the amino acid mimetic monomer advantageouslyprovides desired mechanical strength, biocompatibility, and drugpermeability in the copolymers of the invention.

For purposes of this invention, the term “acrylate monomer” includes,but is not limited to, methacrylates and acrylates.

The hydrophobic monomer can be a methacrylate or other acrylate monomerthat includes hydrophobic groups attached through an ester linkage. Thehydrophobic monomer is typically selected to give the copolymer suitablemechanical strength without crosslinking.

Useful hydrophobic monomers are well known. Examples of suitablehydrophobic monomers include, but are not limited to, methylmethacrylate, ethyl methacrylate, n-propyl methacrylate, isopropylmethacrylate, isobutyl methacrylate, sec-butyl methacrylate,2-ethyl-hexyl methacrylate, n-hexyl methacrylate, cyclohexylmethacrylate, n-hexyl methacrylate, isobornyl methacrylate,trimethylcyclohexyl methacrylate, methyl acrylate, ethyl arylate,n-propyl acrylate, isopropyl acrylate, n-butyl acrylate, isobutylacrylate, sec-butyl acrylate, pentyl acrylate, n-hexyl acrylate,cyclohexyl acrylate combinations of these, and the like.

The amino acid mimetic monomer is selected so that the resulting polymerpossesses protein-like (i.e., polypeptide) properties. Proteins arebiological polymers composed of amino acid monomers. The proteinmolecule derives many of its properties from the side chain or “R group”of the amino acid monomer. The amino acids asparagine and glutamine havepolar R groups that are biocompatible, moderately polar, chemicallystable, and do not interfere with methacrylate polymer synthesis. Thechemical structure of the amino acids asparagine and glutamine are shownbelow.

The R group of asparagine is an acetamide group and the R group ofglutamine is propionamide. In one embodiment, the amino acid mimeticmonomer is an acryloyl or methacryloyl derivative of 2-hydroxyacetamide,3-hydroxypropionamide. The chemical structures of methacrylate monomerswith asparagine and glutamine R groups are shown below.

The invention can also include acrylate monomers with otheracetamide-type R groups that mimic the R group of asparagine orglutamine. Other examples of suitable acetamide-type R groups includealaninamide, lactamide, and glycinamide Examples of monomers with thesespecific R groups are shown below.

These methacrylate monomers can be synthesized by conjugating amethacryloyl group with alaninamide, lactamide, and glycinamide,respectively. In an alternative embodiment, the acrylate is synthesizedby conjugating an acryloyl group with an alaninamide, lactamide, orglycinamide.

The amino acid mimetic monomers of the invention are polar andbiocompatible. Thus, they can advantageously be copolymerized withhydrophobic acrylate monomers. An example of an amino acid mimeticcopolymer according to one embodiment of the invention is shown in thefollowing chemical formula.

In the forgoing formula, R₁ and R₂ may be hydrogen or methyl, the aminoacid mimetic group can be the conjugation product of 2-hydroxyacetamide,3-hydroxypropionamide, alaninamide, lactamide, or glycinamide; thehydrophobic group is a straight chain, branched, unsaturated, or cyclichydrocarbon of one to sixteen carbon atoms; m is in a range from 0.1 to0.99; and n is in a range from 0.01 to 0.9. Unless otherwise stated, themonomers shown in the chemical formula above and other chemical formulasherein can be in any order within the copolymer molecule and the monomerlinkages shown in the chemical formulas only represent that the monomersare part of the same copolymer molecule. Furthermore, unless otherwisestated, the polymeric molecules can include monomers other than thoseshown in the chemical formulas.

The ratio of amino acid mimetic monomer to hydrophobic monomer isselected to yield a copolymer with sufficient mechanical strength foruse as a coating on a medical device. In one embodiment, theconcentration of amino acid mimetic monomer is in a range from about0.5% to about 90% and the concentration of hydrophobic monomer is in arange from about 10% to about 99.5%. The copolymer can be tuned byadjusting the specific monomer ratio to achieve a desired mechanicalstrength, elongation, and drug permeability.

In one embodiment, the concentration of hydrophobic monomer is selectedto yield a thermoplastic copolymer that is substantially free ofcross-linking. While cross-linking can prevent excessive water swelling,cross-linking can be disadvantageous because it limits elongation, whichleads to cracking of the polymer coating. Another benefit of athermoplastic system is that it is simple to process compared tothermoset polymers, which reduces manufacturing costs and can improveproduct quality.

When incorporated into the copolymers of the invention, the amino acidmimetic monomers, and any hydrolysis products that may form in vivo,will be biocompatible since the monomers mimic compounds already presentin humans and other animals Thus, the copolymers of the invention arelikely to be extremely benign. In addition, the amino acid mimeticmonomers make the copolymers of the invention moderately hydrophilic andallow the T_(g) of the hydrated copolymer to be tuned to a desiredtemperature. These features are particularly advantageous for drugelution.

II. Methods of Manufacturing

The method of manufacturing the copolymers of the invention generallyincludes selecting or forming an amino acid mimetic monomer and reactingthe amino acid mimetic monomer with a hydrophobic monomer to form acopolymer that is suitable for coating implantable medical devices. Byvarying the ratio of the hydrophobic monomer to the polar monomer, theproperties of the copolymer may be tuned. In one embodiment, thereaction mixture includes 0.5% to 90% of amino acid mimetic monomer and10% to 99.5% of a hydrophobic monomer, based on the total moles ofmonomer in the reaction mixture. The type and ratio of monomers isselected to yield a copolymer that is biocompatible and mechanicallyrobust.

The copolymers can be synthesized using free radical polymerization,atom transfer radical polymerization, cationic polymerization, anionicpolymerization, iniferter polymerization, or other suitable reactionstechniques. Free radical polymerization can be carried out in a solventusing an initiator. Examples of solvents suitable for carrying out thepolymerization reaction include alcoholic solvents such as, but notlimited to, methanol, ethanol, and isopropyl alcohol. Examples ofsuitable initiators for carrying out the polymerization reaction includeperoxides such as, but not limited to, benzoyl peroxide, and azocompounds. A specific example of a suitable initiator is2,2′-azo-bis(2-methylproprionitrile). Those skilled in the art arefamiliar with the conditions for carrying out the foregoingpolymerization reactions and other similar polymerization reactionssuitable for yielding the copolymers of the invention.

An alternate path to synthesizing the polymer includes copolymerizingmethacrylic acid, or acrylic acid, and the hydrophobic monomer to yielda copolymer with the following structure.

The polymerization reaction to produce this molecule can be carried outusing the same polymerization techniques described previously. Next,2-hydroxyacetamide, 3-hydroxypropionamide, alaninamide, lactamide, orglycinamide, or other suitable acetamide group is coupled to the carboxygroups of the methacrylic or acrylic acid. Several coupling chemistriescan be used to perform the coupling reaction, including, but not limitedto, conversion to an acid chloride or use of carbodiimides. For thecoupling of amino acid mimetic groups with amine functional groups, anexample method is to form the n-hydroxysuccinimidyl ester of the polymerby coupling N-hydroxysuccinamide with dicyclohexyl carbodiimide (DCC).The amino-functional amino acid mimetic group such as, but not limitedto glycinamide, can then be coupled to the activated carboxyl group. Anexample of a technique that can be used to couple the hydroxylfunctional moieties is DCC and 4-(dimethylamino)pyridinium (DPTS) asdescribed in M. Trollsas, J. Hedrick, Macromolecules 1998, 31,4390-4395.

In yet another alternative embodiment, the amino acid mimetic monomercan be synthesized by first forming a homopolymer of a hydrophobicmonomer. The homopolymer can then be subjected to acid catalysis with anacetamide acid such as, but not limited to 2-hydroxyacetamide. Thisreaction exchanges some of the hydrophobic groups as ethanol andreplaces them with the acetamide group by transesterification.Byproducts, including ethanol, can be removed by distillation, forexample.

In one embodiment, the copolymer compositions are manufactured to have adesired T_(g), when hydrated. The T_(g) of the copolymer can becalculated by knowing the amount of water absorbed and the T_(g) derivedfrom measurements of the homopolymer of the respective monomers. In anembodiment, the T_(g) is calculated using the Fox equation, which isshown below.

$\frac{1}{T_{g}^{Polymer}} = {\frac{W^{PC}}{T_{g}^{PC}} + \frac{W^{Water}}{T_{g}^{Water}} + \frac{W^{Methacrylate}}{T_{g}^{Methacrylate}}}$

T_(g)=Glass transition temperature of the homopolymer or pure material.

T_(g) ^(water)=−40° C.

W=Weight fraction of the components.

Once the water absorption of the polymer is known, which is usuallymeasured experimentally, the copolymer T_(g) can be estimated with thedesired target. In one embodiment the desired target T_(g) is in a rangefrom about −30° C. to about 37° C. when in the fully hydrated state. Inanother range, the T_(g) is between about 0° C. and about 37° C. whenhydrated. With a T_(g) of less than 37° C., the copolymers of theinvention will have a high degree of polymer mobility when placed invivo. This feature allows the surface of the polymer to enrich inhydrophilic monomer content, which is advantageous for biocompatibility.

In an alternative embodiment, the co-polymer is designed to have adesired T_(g) for the polymer in the dry state. In an embodiment, theT_(g) of the polymer when dry is in a range from about −30° C. to about100° C. or alternatively in a range from 0° C. to about 70° C.

The polymerization reaction can be controlled to produce the copolymerswith a desired molecular weight. In one embodiment, the number averagemolecular weight of the copolymer is in the range from about 20K toabout 800K, and in another range from about 100K to about 600K.

In an alternative embodiment, the molecular weight of the polymer isselected to provide adhesion. In this embodiment, the number averagemolecular weight can be in a range from about 2K to about 200K. Theadhesive polymer can be used on medical devices that benefit from anadhesive polymer coating.

In an embodiment, the copolymers are manufactured substantially free ofcross-linking. Copolymers manufactured according to the invention canhave sufficient mechanical strength when hydrated that cross-linking isnot necessary for making a polymer coating suitable for coating animplantable device. The absence of cross-linking in the copolymers ofthe invention gives the copolymers improved elasticity, particularlywhen dry, which reduces the likelihood of cracking during assembly anduse.

III. Use of Coatings on Implantable Devices

The foregoing copolymers are suitable for use on any medical device thatis compatible with polymer coatings. The copolymers can be used alone asa coating or can be combined with other polymers or agents to form apolymer coating. For example, the polymers may be blended withpoly(vinyl pyrrolidinone), poly(n-butyl methacrylate), poly(n-butylmethacrylate) copolymers, methacrylate polymers, acrylate polymers,and/or a terpolymers of hexyl methacrylate, vinyl acetate, and vinylpyrrolidinone.

The polymer coatings can be applied to a medical device using anytechniques known to those skilled in the art or those that may bedeveloped for applying a coating to a medical device. Examples ofsuitable techniques for applying the coating to the medical deviceinclude spraying, dip coating, roll coating, spin coating, powdercoating, inkjet printing, and direct application by brush or needle. Oneskilled in the art will appreciate the many different techniques inpowder coating. The copolymers can be applied directly to the surface ofthe implant device, or they can be applied over a primer or othercoating material.

In one embodiment, the polymer coating is applied to a medical deviceusing a solvent-based technique. The polymer can be dissolved in thesolvent to form a solution, which can be more easily applied to themedical device using one or more of the above mentioned techniques oranother technique. Thereafter substantially all or a portion of thesolvent can be removed to yield the polymer coating on a surface of themedical device.

Examples of suitable solvents that can be used with the copolymers ofthe invention include, but are not limited to, dimethylacetamide (DMAC),dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide(DMSO), cyclohexanone, xylene, toluene, acetone, n-butanol, i-propanol,methyl ethyl ketone, propylene glycol monomethyl ether, methyl t-butylketone, methyl isobutyl ketone, ethyl acetate, n-butyl acetate, ethanol,methanol, chloroform, trichloroethylene, 1,1,1-trichloreoethane,methylene chloride, and dioxane. Solvent mixtures can be used as well.Representative examples of the mixtures include, but are not limited to,DMAC and methanol (50:50 w/w); water, i-propanol, and DMAC (10:3:87w/w); i-propanol and DMAC (80:20, 50:50, or 20:80 w/w); acetone andcyclohexanone (80:20, 50:50, or 20:80 w/w); acetone and xylene (50:50w/w); and 1,1,2-trichloroethane and chloroform (80:20 w/w).

Examples of suitable implantable devices that can be coated with thecopolymers of the invention include coronary stents, peripheral stents,catheters, arterio-venous grafts, by-pass grafts, pacemaker anddefibrillator leads, anastomotic clips, arterial closure devices, patentforamen ovale closure devices, and drug delivery balloons The copolymersare particularly suitable for permanently implanted medical devices.

The implantable device can be made of any suitable biocompatiblematerials, including biostable and bioabsorbable materials. Suitablebiocompatible metallic materials include, but are not limited to,stainless steel, tantalum, titanium alloys (including nitinol), andcobalt alloys (including cobalt-chromium-nickel andcobalt-chromium-tungsten alloys). Suitable nonmetallic biocompatiblematerials include, but are not limited to, polyamides, fluoropolymers,polyolefins (i.e. polypropylene, polyethylene etc.), nonabsorbablepolyesters (i.e. polyethylene terephthalate), and bioabsorbablealiphatic polyesters (i.e. homopolymers and copolymers of lactic acid,glycolic acid, lactide, glycolide, para-dioxanone, trimethylenecarbonate, c-caprolactone, and the like, and combinations of these).

The copolymers are particularly advantageous as a coating for stents dueto their elongation properties, which allow the coated stent to becrimped and expanded without cracking the coating. The stents can becomposed of wire structures, flat perforated structures that aresubsequently rolled to form tubular structures, or cylindricalstructures that are woven, wrapped, drilled, etched or cut.

FIG. 1A shows an example stent 10 coated with a copolymer includingamino acid mimetic monomers. Stent 10 includes a generally tubular body12 with a lumen. The struts of body 12 (e.g. strut 14) provide asupporting structure for coating the polymers of the invention.

FIG. 1B illustrates a cross-section of the stent of FIG. 1A coated witha polymer coating 16 according to an embodiment of the invention. Thepolymer coating 16 can be conformal as in FIG. 1B. Alternatively, thecoating can be ablumenal, luminal, or any combination thereof. In oneembodiment, the copolymers of the invention can be elastic at bodytemperatures and can therefore expand without cracking as the stentexpands during use.

The polymer coated stents of the invention can be self-expanding orballoon expandable. The copolymer coatings of the invention can beparticularly advantageous for self-expanding stents. Self-expandingstents are typically restrained by a sheath that is removed duringdeployment of the stent. The copolymers of the invention have improvedmechanical strength to better withstand the friction exerted on thepolymer as the sheath is removed.

In one embodiment, a bioactive agent is associated with the coatedmedical devices. The bioactive agent can be associated with a base coat,top coat, mixed with the novel copolymers of the invention, and/orincorporated or otherwise applied to a supporting structure of themedical device.

The bioactive agent can have any therapeutic effect. Examples ofsuitable therapeutic properties include anti-proliferative,anti-inflammatory, antineoplastic, antiplatelet, anti-coagulant,anti-fibrin, antithrombonic, antimitotic, antibiotic, antiallergic andantioxidant properties.

Examples of suitable bioactive agents include synthetic inorganic andorganic compounds, proteins and peptides, polysaccharides and othersugars, lipids, DNA and RNA nucleic acid sequences, antisenseoligonucleotides, antibodies, receptor ligands, enzymes, adhesionpeptides, blood clot agents, including streptokinase and tissueplasminogen activator, antigens, hormones, growth factors, ribozymes,retroviral vectors, anti-proliferative agents including rapamycin(sirolimus), 40-O-(2-hydroxyethyl)rapamycin (everolimus),40-O-(3-hydroxypropyl)rapamycin, 40-O-(2-hydroxyethyoxy)ethylrapamycin,40-O-tetrazolylrapamycin (zotarolimus, ABT-578),40-epi-(NI-tetrazolyl)-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, Biolimus A9 (biosensorsInternational, Singapore), deforolimus, AP23572 (Ariad Pharmaceuticals),paclitaxel, docetaxel, methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride, mitomycin,antiplatelet compounds, anticoagulants, antifibrin, antithrombinsincluding sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin, prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, thrombin inhibitorsincluding Angiomax ä, calcium channel blockers including nifedipine,colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega3-fatty acid), histamine antagonists, lovastatin, monoclonal antibodies,nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors,suramin, serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine, nitric oxide or nitric oxide donors, super oxidedismutases, super oxide dismutase mimetic, estradiol, anticancer agents,dietary supplements including vitamins, anti-inflammatory agentsincluding aspirin, tacrolimus, dexamethasone, dexamethasone acetate,dexmethasone phosphate, momentasone, cortisone, cortisone acetate,hydrocortisone. prednisone, prednisone acetate, betamethasone,betamethasone acetate, clobetasol, cytostatic substances includingangiopeptin, angiotensin converting enzyme inhibitors includingcaptopril, cilazapril or lisinopril, antiallergic agents is permirolastpotassium, alpha-interferon, bioactive RGD, and genetically engineeredepithelial cells. Other bioactive agents which are currently availableor that may be developed in the future for use with drug eluting stentsmay likewise be used and all are within the scope of this invention.

The medical devices of the invention can be used in any vascular,tubular, or non-vascular structure in the body. In an embodiment, acoated stent can be used in, but is not limited to use in, neurological,carotid, coronary, aorta, renal, biliary, ureter, iliac, femoral, andpopliteal vessels.

IV. Examples

The following are specific examples of copolymers of amino acid mimeticmonomers and hydrophobic monomers. The following copolymers are usefulfor coating implantable medical devices.

Example 1

Example 1 describes a copolymer of poly(acetamidemethacrylate-co-n-butyl methacrylate). The polymer has the followingformula.

In the foregoing formula, m is in a range from 0.1 to 0.99 and n is in arange from 0.01 to 0.9. The use of poly(n-butyl methacrylate) monomer isparticularly advantageous since the homopolymer of PBMA is currentlybeing used in implantable medical devices and is thus known to bebiocompatible.

Example 2

Example 2 describes a copolymer of poly(3-methacryloylpropionamide-co-ethyl methacrylate). The chemical formula ofpoly(3-methacryloyl propionamide-co-ethyl methacrylate) is shown below.

In the foregoing formula, m is in a range from about 0.1 to about 0.98and n is in a range from about 0.02 to about 0.9. The higher T_(g) ofthe alkyl methacrylate monomer will enable a harder, stronger coating atthe expense of elasticity as compared to Example 1.

Example 3

Example 3 describes a copolymer of poly(alaninamidemethacrylate-co-n-propyl methacrylate). The copolymer of Example 3 hasthe following formula.

In the foregoing formula, m is in a range from about 0.1 to about 0.995and n is in a range from about 0.005 to about 0.9.

Example 4

Example 4 describes a copolymer of poly(lactamidemethacrylate-co-n-butyl methacrylate). The copolymer of Example 4 hasthe following formula.

In the foregoing formula, m is in a range from about 0.1 to about 0.995and n is in a range from about 0.005 to about 0.9. The use ofpoly(n-butyl methacrylate) monomer is particularly advantageous sincethe homopolymer of PBMA is currently being used in implantable medicaldevices and is thus known to be biocompatible.

Example 5

Example 5 describes a copolymer of poly(glycinamidemethacrylate-co-n-hexyl methacrylate). The copolymer of Example 5 hasthe following formula.

In the foregoing formula, m is in a range from about 0.1 to about 0.995and n is in a range from about 0.005 to about 0.9.

Example 6

Example 6 describes a method for manufacturing a coated stent using oneor more of the polymers of Examples 1-5. In a first step, a primercoating is applied to the stent. A primer solution including betweenabout 0.1 mass % and about 15 mass %, (e.g., about 2.0 mass %) ofpoly(n-butyl methacrylate) (PBMA) and the balance, a solvent mixture ofacetone and cyclohexanone (having about 70 mass % of acetone and about30 mass % of cyclohexanone) is prepared. The solution is applied onto astent to form a primer layer.

To apply the primer layer, a spray apparatus, (e.g., Sono-Tek MicroMistspray nozzle, manufactured by Sono-Tek Corporation of Milton, N.Y.) isused. The spray apparatus is an ultrasonic atomizer with a gasentrainment stream. A syringe pump is used to supply the coatingsolution to the nozzle. The composition is atomized by ultrasonic energyand applied to the stent surfaces. A useful nozzle to stent distance isabout 20 mm to about 40 mm at an ultrasonic power of about one watt toabout two watts. During the process of applying the composition, thestent is optionally rotated about its longitudinal axis, at a speed of100 to about 600 rpm, for example, about 400 rpm. The stent is alsolinearly moved along the same axis during the application.

The primer solution is applied to a 15 mm Triplex, N stent (availablefrom Abbott Vascular Corporation) in a series of 20-second passes, todeposit, for example, 20 ug of coating per spray pass. Between the spraypasses, the stent is allowed to dry for about 10 seconds to about 30seconds at ambient temperature. Four spray passes can be applied,followed by baking the printer layer at about 80° C. for about 1 hour.As a result, a primer layer can be formed having a solids content ofabout 80 μg. For purposes of this invention, “Solids” means the amountof the dry residue deposited on the stent after all volatile organiccompounds (e.g., the solvent) have been removed.

In a separate step, a copolymer solution is prepared. The copolymersolution includes one or more of the copolymer of Examples 1, 2, 3, 4,or 5. The solution is prepared by dissolving between about 0.1 mass %and about 15 mass %, (e.g., about 2.0 mass %) of the copolymer in asolvent. The solvent can be a mixture of about 50 mass % ethanol andabout 50 mass % n-butanol.

In a manner similar to the application of the primer layer, thecopolymer solution is applied to a stent. Twenty one spray passes areperformed with a coating application of 10 μg per pass, with a dryingtime between passes of 10 seconds, followed by baking the copolymerlayer at about 60° C. for about 1 hour, to form a layer having a solidscontent between about 30 μg and 750 μg, (e.g., about 210 μg).

Example 7

Example 7 describes a method for manufacturing a drug eluting stentaccording to an embodiment of the invention. The medical device ismanufactured using the same method as in Example 6, except that insteadof the copolymer solution, a polymer-therapeutic solution is preparedand applied using the following formula.

A drug-including formulation is prepared that includes:

(a) between about 0.1 mass % and about 15 mass %, (e.g., about 2.0 mass%) of the copolymer of one or more of Example 1-5;

(b) between about 0.1 mass % and about 2 mass %, for example, about 1.0mass % of a therapeutic agent. In one embodiment, the therapeutic agentis ABT-578 (available from Abbott Vascular Corp. of Chicago, Ill.); and

(c) the balance, a solvent mixture including about 50 mass % of ethanoland about 50 mass % of n-butanol.

The drug-including formulation is applied to the stent in a mannersimilar to the application of the copolymer solution in Example 6. Theprocess results in the formation of a drug-polymer reservoir layerhaving a solids content between about 30 μg and 750 μg, (e.g., about 210μg) and a drug content of between about 10 μg and about 250 μg, (e.g.,about 70 μg).

The invention may be embodied in other specific forms without departingfrom its spirit or essential characteristics. The described embodimentsare to be considered in all respects only as illustrative and notrestrictive. The scope of the invention is, therefore, indicated by theappended claims rather than by the foregoing description. All changeswhich come within the meaning and range of equivalency of the claims areto be embraced within their scope.

Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein.

1. A medical device comprising a supporting structure having a coatingassociated therewith, the coating comprising a polymer having theformula,

in which, the hydrophobic group is a straight chain, branched,unsaturated or cyclic hydrocarbon of one to sixteen carbon atoms; theamino acid mimetic group is an acetamide, a propionamide, analaninamide, a lactamide, or glycinamide; R₁ and R₂ are independently ahydrogen or a methyl group; m is in a range from about 0.1 to about0.995; and n is in a range from about 0.005 to about 0.9
 2. The medicaldevice as in claim 1, in which the amino acid mimetic group is selectedfrom the group consisting of acetamide, propionamide, alaninamide,lactamide, glycinamide, or a combination thereof.
 3. The medical deviceas in claim 1, in which the hydrophobic group is selected from the groupconsisting of a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, 2-ethyl-hexyl, n-hexyl, cyclohexyl, n-hexyl, isobornyl, ortrimethylcyclohexyl, and combinations thereof.
 4. The medical device asin claim 1, in which R₁ and R₂ are methyl groups.
 5. The medical deviceas in claim 1, in which the glass transition temperature of the polymerwhen hydrated is in a range from about −30° C. to about 37° C.
 6. Themedical device as in claim 1, in which the glass transition temperatureof the polymer when dry is in a range from about −30° C. to about 100°C.
 7. The medical device as in claim 1, in which the polymer having achemical formula of

in which, m is in a range from about 0.1 to about 0.995; n is in a rangefrom about 0.005 to about 0.9; and m+n=1.
 8. The medical device as inclaim 1, in which the polymer having a chemical formula of

in which, m is in a range from about 0.1 to about 0.995; n is in a rangefrom about 0.005 to about 0.9; and m+n=1.
 9. The medical device as inclaim 1, wherein the polymer having a chemical formula of

in which, m is in a range from about 0.1 to about 0.995; n is in a rangefrom about 0.005 to about 0.9; and m+n=1.
 10. The medical device as inclaim 1, in which the polymer having a chemical formula of

in which, m is in a range from about 0.1 to about 0.995; n is in a rangefrom about 0.005 to about 0.9; and m+n
 1. 11. The medical device as inclaim 1, in which the polymer having a chemical formula of

in which, m is in a range from about 0.1 to about 0.995; and n is in arange from about 0.005 to about 0.9
 12. The medical device as in claim1, in which the number average molecular weight of the polymer is in arange from about 20K to about 800K.
 13. The medical device as in claim1, in which the number average molecular weight of the polymer is in arange from about 100K to about 600K.
 14. The medical device as in claim1, in which the number average molecular weight of the polymer is in arange from about 2K to about 200K.
 15. The medical device as in claim 1,in which the polymer is substantially free of cross-linking.